Journal of Fungi Review Host Immune Defense upon Fungal Infections with Mucorales: Pathogen-Immune Cell Interactions as Drivers of Inflammatory Responses Dolly E. Montaño 1,2 and Kerstin Voigt 1,2,* 1 Jena Microbial Resource Collection, Leibniz Institute for Natural Product Research and Infection Biology—Hans Knöll Institute (HKI), 07745 Jena, Germany; [email protected] 2 Institute of Microbiology, Friedrich Schiller University Jena, 07743 Jena, Germany * Correspondence: [email protected]; Tel.: +49-3641-532-1395 Received: 14 August 2020; Accepted: 15 September 2020; Published: 17 September 2020 Abstract: During the last few decades, mucormycosis has emerged as one of the most common fungal infections, following candidiasis and aspergillosis. The fungal order responsible for causing mucormycosis is the Mucorales. The main hallmarks of this infection include the invasion of blood vessels, infarction, thrombosis, and tissue necrosis, which are exhibited at the latest stages of the infection. Therefore, the diagnosis is often delayed, and the rapid progression of the infection severely endangers the life of people suffering from diabetes mellitus, hematological malignancies, or organ transplantation. Given the fact that mortality rates for mucormycosis range from 40 to 80%, early diagnosis and novel therapeutic strategies are urgently needed to battle the infection. However, compared to other fungal infections, little is known about the host immune response against Mucorales and the influence of inflammatory processes on the resolution of the infection. Hence, in this review, we summarized our current understanding of the interplay among pro-inflammatory cytokines, chemokines, and the host-immune cells in response to mucoralean fungi, as well as their potential use for immunotherapies. Keywords: zygomycosis; phagocytosis; phagocytes; macrophages; monocytes; epi- and endothelium; Mucoromycotina; Rhizopus; Rhizomucor; Mucor; Lichtheimia; innate immune system 1. Introduction The life-threatening infection mucormycosis is currently the third most common invasive fungal infection [1,2]. Most of the incidences occur in patients with diabetes mellitus, hematological malignancies, organ transplantation, and in few cases also in immunocompetent individuals [1–4]. Mucormycosis is caused by fungi belonging to the order Mucorales, mainly by Rhizopus, Mucor, and Lichtheimia (ex Absidia) species (Figure1)[ 5,6]. This infection is characterized by a fast invasion of blood vessels that further leads to infarction, thrombosis, and tissue necrosis. As a consequence, most of the patients suffer devastating results, such as massive removal of infected tissue, loss of organ functionality, and death in the worse scenario [7,8]. Contrary to candidiasis and invasive aspergillosis, mucormycosis cases are normally diagnosed in advanced stages of the infection. Furthermore, treatments against this infection are limited to liposomal amphotericin B, isavuconazole, and posaconazole, which represents a disadvantage in the case of antifungal drug resistance [5,9]. Although mucormycosis has become an emerging fungal infection, compared to the most common fungal invasive infections, aspergillosis and candidiasis, little is known about the host immune response against Mucorales [4,10]. Hence, understanding the molecular mechanisms involved in the recognition and immune response to Mucorales could provide novel insights for antifungal therapies and diagnosis. J. Fungi 2020, 6, 173; doi:10.3390/jof6030173 www.mdpi.com/journal/jof J. Fungi 2020, 6, 173 2 of 14 Therefore,J. Fungi in this 2020, review,6, x FOR PEER we REVIEW will summarize our current understanding of the molecular2 of interaction15 among host cells in response to mucoralean fungi. In particular, we will focus on the production of involved in the recognition and immune response to Mucorales could provide novel insights for cytokinesantifungal and chemokines, therapies and which diagnosis. enables Therefore, communication in this review, among we leukocytes,will summarize and our plays current an essential role in theunderstanding regulation ofof ditheff erentmolecular cellular interaction processes among during host cells infection, in response such to mucoralean as phagocytes fungi. recruitment, In inflammation,particular, antigen we presentation,will focus on activation,the production and immuneof cytokines cell maturationand chemokines, [11]. which Moreover, enables during this review, wecommunication will emphasize among three leukocytes, relevant and plays aspects an essentia of thel hostrole in response the regulation upon of Mucoraleandifferent cellular infections: processes during infection, such as phagocytes recruitment, inflammation, antigen presentation, (i) the cytokineactivation, profile and immune produced cell maturation by immune [11]. Moreov cells iner, responseduring this toreview, Mucorales. we will emphasize (ii) The three influence of cytokinesrelevant and chemokines aspects of the onhost the response activation upon Mucoralean of adaptive infections: immune i) the cells. cytokine (iii) profile The potential produced usage of cytokinesby as immune an adjuvant cells in forresponse immunotherapies to Mucorales. ii) during The influence invasive of cytokines mucormycosis. and chemokines We will on notthe address virulenceactivation factors andof adaptive specific immune cell-mediated cells. iii) The response potential to usage Mucorales, of cytokines since as thesean adjuvant topics for have been immunotherapies during invasive mucormycosis. We will not address virulence factors and specific previously summarized [12,13]. cell-mediated response to Mucorales, since these topics have been previously summarized [12,13]. Figure 1.FigureThe most 1. The common most common pathogenic pathogenic mucoralean mucoralean fungi fungi.. RhizopusRhizopus oryzae oryzae (syn.: (syn.:RhizopusRhizopus arrhizus), arrhizus), Mucor circinelloides, and Lichtheimia corymbifera are the most frequently reported causative agents of Mucor circinelloides, and Lichtheimia corymbifera are the most frequently reported causative agents mucormycosis. The left panel depicts the colony morphologies of four-week-old R. oryzae and L. of mucormycosis.corymbifera cultivated The left on panel malt depictsextract agar, the as colony well as morphologiesthe colony morphology of four-week-old of one-week-oldR. M. oryzae and L. corymbiferacircinelloidescultivated cultivated on malton potato extract dextrose agar, agar. as wellThe asright the panel colony represents morphology the corresponding of one-week-old M. circinelloidesmicromorphologiescultivated including on potato spor dextroseangia (marked agar. with The arrows), right in panel which representsthe sporangiospores the corresponding are micromorphologiesproduced. Sporangium including of R. sporangia oryzae presents (marked a dark-brown with coloration, arrows), while in which M. circinelloides the sporangiospores exhibits a are yellow color and L. corymbifera a dark grey pigmentation. produced. Sporangium of R. oryzae presents a dark-brown coloration, while M. circinelloides exhibits a yellow color and L. corymbifera a dark grey pigmentation. 2. Inflammation in Antifungal Response Inflammation has been traditionally defined according to its main features: redness, warmth, pain, and swelling. However, one of the latest definition of inflammation includes its protective role in response to invading pathogens or endogenous signals, resulting in the elimination of the initial cause of injury, clearance, and tissue repair [14]. Furthermore, the activation and resolution of the inflammatory response are strictly regulated to protect the organism from collateral damages. In this regard, specialized cell-surface receptors known as pattern-recognition receptors (PRRs) activate J. Fungi 2020, 6, 173 3 of 14 inflammatory cascades upon the recognition of pathogen-associated molecular patterns (PAMPs) or endogenous signals, such as damage-associated molecular patterns (DAMPs) [15]. Consequently, activation of PRRs triggers the release of proinflammatory cytokines and chemokines—which are secreted proteins that exert further pro-inflammatory cascades and recruit additional immune cells to the site of infection [11]. In the case of an antifungal inflammatory-mediated response, PRRs of the host-cells recognize conserved microbial structures known as microbial associated molecular patterns (MAMPs), which are mainly found in the fungal cell-wall and comprise β-1,3-glucan, chitin, mannans, mannoproteins, and unmethylated DNA [16]. Furthermore, fungal growth and invasion by pathogenic fungi also induce local damage, promoting the release of DAMPs and amplifying the inflammatory response [17]. 3. Clinical Features of Inflammation in Mucormycosis Angioinvasion, thrombosis, and tissue necrosis are the most common hallmarks of mucormycosis [7]. However, inflammatory responses accompanied by these hallmarks have not been widely characterized in clinical trials. A study by Ben-Ami et al. analyzed histopathologic features in cancer patients diagnosed with pulmonary mucormycosis (PM). The authors found that 100% of the patients with PM showed angioinvasion; on the contrary, only 30% of the patients exhibited inflammatory infiltrates, such as aggregates of macrophages in the margin of necrotic tissues [18]. Furthermore, patients within the same cohort that underwent allogeneic hematopoietic stem cell transplantation (HSCT) had more inflammatory cell infiltration compared to non-HSCT patients